Preparation for the prophylaxis of restenosis

ABSTRACT

The invention relates to a preparation for restenosis prevention. The preparations for restenosis prevention known as yet do not reach sufficient active agent concentrations in the affected sections of the vascular walls as higher doses cause undesirable side effects. The present invention is a preparation to which at least one antihyperplastic agent is added that has a distribution ratio between butanol and water .gtoreq.0.5. The lipophilic active agent is absorbed by the vascular wall fast and in sufficient quantity. The preparation may be a liquid that can pass through capillaries and may contain a contrast agent so that the active agent is transferred into the vascular wall without any additional effort while the usually required contrast radiograms are taken. The preparation may also be applied to a catheter.

DESCRIPTION

The invention relates to a preparation for restenosis prevention and itsapplication to an angiography catheter.

Stenoses of blood vessels are a major cause of morbidity and morality.Local stenoses or occlusions of larger vessels up to ca. 2 mm indiameter can be dilated back to their original lumen in many instancesusing inflatable balloon catheters. High pressures are applied whendoing this, which may result in lacerations of the thickened vascularwalls that are squeezed and displaced into the surrounding tissue. Insome of these operations, tubular perforated metal supports (stents) areimplanted to keep the vessels open. The vascular walls treated in thisway frequently respond by increased growth in thickness that is similarto developing a scar within a few weeks and months. As a result and dueto advancing arteriosclerosis, these vessels may relatively soon becomestenosed again (restenosis). Restenosis is a severe medical problem thatcauses high costs.

A proven clinical method to prevent restenosis is irradiation of theaffected vascular wall sections with a high dosage of X-rays(extracorporal sources or intraluminal radioisotopes) immediately afterthe surgery.

Major disadvantages of irradiation are the required precautions whenhandling preventive radiation dosages. Many other methods for preventingpremature restenosis have been tested in labs and clinical practice butas yet without any major breakthrough [Bult H. Restenosis: A challengefor pharmacology. Tips 21 pp. 274-279, 2000]. Good results were onlyachieved using drug-releasing stents. For this method to be effective,stents have to be implanted so that restenosis cannot be prevented whenthe vessel is just dilated and no stent is implanted.

Inhibition of mitosis, reactive vascular wall thickening and restenosishas been described for a great number of drugs: Important principles ofaction are inhibition of platelet aggregation, enzyme inhibition,inhibition of mitosis, cytostatics, and corticoids. Favorable resultswere achieved in vitro and partly in animal experiments but have notbeen confirmed in clinical tests. A frequent explanation offered is thatactive agent concentrations in the affected sections of the vascularwall are insufficient. This is particularly true for oral andintravenous administration where side effects prevent higher doses. Asan alternative, administration using specific catheters was attemptedwherein these catheters either press the drug solution through the poresof a tight-sitting balloon directly into the vascular wall or blocksupply and discharge in a vessel section and expose the vessel wall tothe drug solution for some time [Herdeg, C., M. Oberhoff, D. I.Siegel-Axel, A. Baumbach, A. Blattner, A. Kuttner, S. Schroder, K. R.Karsch: Paclitaxel: Ein Chemotherapeutikum zur Restenoseprophylaxe?Experimentelle Untersuchungen in vitro und in vivo. Z Kardiol 89 pp.390-397, 2000]. Drug exposure of previously dilated vessel sections thatwas effective over a longer period of time was achieved by the slowrelease of active agents from coated stents. However, the problem ofachieving sufficient active agent concentrations over a sufficientexposure time in the vessel sections requiring treatment remains thesame with all these methods. Hydrophilic active agents are quicklywashed out of tissues [Baumbach, A., C. Herdeg, M. Kluge, M. Oberhoff,M. Lerch, K. K. Haase, C. Wolter, S. Schroder, K. R. Karsch: Local drugdelivery: Impact of pressure, substance characteristics, and stenting ondrug transfer into the arterial wall. Cathet Cardiovasc Intervent 47 pp.102-106, 1999]. Repeated administration is impossible because of theinvasive access using catheters. Lipophilic active agents do notdissolve well enough in vessel-compatible aqueous media or are kept insolution as micelles or liposomes; these micelles or liposomes are onlyslowly absorbed by the tissue. Administration using special cathetersthat interrupt the blood flow for some time or press the active agentsolution under high pressure into the vascular wall first of all causesadditional tissue damage and intensifies reactive hyperplasia.

Coated, drug-releasing stents are difficult to produce in constantquality, they contain only very low active agent quantities due to theirlight weight and delicate design and are not suitable for proximal anddistal treatment of the vascular sections at risk of restenosis a fewmillimeters around the stent. If a stent was implanted at an earliertime, and there is stenosis in its lumen, this can be removed byinflating a balloon catheter. This implantation of a second stent intothe lumen of the first stent to prevent vessel wall hyperplasia as aconsequence of dilatation is undesirable so that there is no effectivemethod of restenosis prevention for this case. The same applies whenthere is no indication for implanting a stent after angioplasty or whenhyperplastic vessel processes are taking place without clear stenosis ofthe lumen so that neither vessel dilatation nor stent implantation arerequired. Some of these vessel wall changes may cause sudden, mostlythrombotic occlusions. In this case, too, a method independent of stentimplantation for inhibiting pathological vessel wall changes isdesirable.

Active agents that were tested with some success in laboratory settingsare heparin and hirudin derivatives, prostacyclins, corticoids,rapamycin, colchicine, and paclitaxel.

In most cases, the active agents were applied to stents; wheneversolutions were used, these were aqueous solutions or, for the poorlywater-soluble paclitaxel(4,10-β-diacetoxy-13-α-((2R,3S)-3-ben-zamido-2-hydroxy-3-phenylpropionyloxy)-2α-benzoyloxy-5-β,20-epoxy-1,7-β-dihydroxy-11-taxene-9-one),aqueous solutions with an ethanol or cremophor additive. Micelles areformed when using cremophor [poly(oxyethylene)-35-castor oil] that canlargely be avoided when using ethanol.

Suspensions or emulsions with relatively large-sized particles inaqueous cytostatic solutions with or without an added contrast agenthave been described for direct injection into tumor-feeding bloodvessels. These preparations are used to close tumor vessels and forsimultaneous cytostatic treatment. Closing the vessels is directlyopposed to the purpose of this invention.

It is the problem of this invention to provide agents for the localtreatment of potentially hyperproliferative tissue that can be handledeasily and do not harm the patient.

Based on the state of the art, this problem is solved according to theinvention by a preparation containing at least one antihyperplasticagent with a distribution ratio between butanol and water of ≧0.5, andby inserting said preparation in an agent for enhancing the imaging ofarteries and veins or by applying it to a catheter.

The concept of the invention is based on the observation that activeagents from adequately concentrated solutions, gels or other matricesare absorbed fast and in sufficient quantities by a vessel wall unlessthey are enclosed in outwardly hydrophilic micelles by solubilitypromoters. When the active agents are lipophilic (butanol to aqueousbuffer solution (pH 7) distribution ratio ≧0.5, preferably ≧1 and ≧5particularly preferred, or octanol to aqueous buffer solution (pH 7)distribution ratio ≧1, preferably ≧10, and ≧50 particularly preferred),and/or reversibly (>10%, preferably >50%, >80% particularly preferred)and/or irreversibly bind to cell components (such as paclitaxel,probucol (4,4′-isopropylidenebisthio)bis(2,6-di-tert-butylphenol),porphyrin derivatives), the retention time in the blood vessel whenadministered during vessel dilatation and optional stent implantation issufficient for the treatment effect. Prevention of reduction of initialreactive hyperplasia as a consequence of vascular injury prevents thevessel wall from growing too thick over many months. Surprisingly, thepreparations according to the invention did not require longer exposureof the tissue to be treated or indirect infiltration and additionalinjury of the vessel wall.

Contrast agents were selectively injected into the affected vesselsseveral times during angioplasty and stent implantation to determinepositioning, degree and form of the stenosis, to specify the exactposition of the dilatation catheter, evaluate dilatation success, and,optionally, to implant a stent of appropriate thickness and length. Byadding the active agents or their preparations that are suited for thepurpose to the contrast agents used for diagnostic purposes, the activeagent is transferred into the vascular wall with each injection ofcontrast agent, without additional effort or damage to the vessels. Theentire vessel section imaged for diagnostic purposes is treatedincluding the area in front of the stenosis and the area away from itscenter. This has the major benefit that critical zones upstream anddownstream from the dilated stenosis and optional stent implantation arenot excluded from treatment.

If the injection of contrast media is not required or undesirable,solutions of lipophilic active agents in other aqueous carriers can beused without adding micelle-forming substances. One requirement is thatthese solutions contain a higher active agent concentration than thesaturation concentration in the aqueous medium. This can be achieved byadding organic solvents that form few or no micelles such as ethanol orDMSO and/or by dissolving the active agents under conditions that arenot beneficial for storage and administration (e.g. heating, mixing withconcentrated active agent solutions in organic solvents) to formsufficiently stable oversaturated solutions.

In some cases, solubility of the lipophilic active agents in thecontrast agent solutions or the stability of oversaturated solutions aresurprisingly improved. Another surprising effect due to the contrastagents is enhanced adhesion and absorption of active agents by vesselwalls and good local tolerance of some substances of extreme systemictoxicity in sensitive vessel sections.

When active agent and contrast medium are incompatible or when theactive agent does not dissolve properly in the contrast medium, theactive agent solution can also be directly infused or injected throughthe diagnostic catheter into the respective vessel. It is preferred touse similar volumes as they are common for vessel imaging using contrastmedia through catheters [Elke M: Kontrastmittel in der radiologischenDiagnostik, pp. 113-119, 3rd edition, Georg Thieme Verlag Stuttgart NewYork, 1992].

Contrast agents are solutions, suspensions or emulsions well toleratedby vessels that can be used to enhance the representation of bloodvessels or the bloodstream in radiograms, sonograms, optical imaging ormagnet resonance imaging.

These contrast agents include Visipaque 320 (iodixanol), Ultravist 370(iopromide), Omnipaque 350 (iohexol) or Solutrast 370 (iopamidol) orMagnevist (gadolinium-DPTA) or Gadovist 1M (Gd-DO3A-butrol).

Active agents can be all substances suitable for inhibiting cell growth,cell multiplication and hyperplastic proliferation provided they meetthe criteria defined above regarding lipophilia and/or binding to tissuecomponents. Inasmuch as some active agents are not sufficientlylipophilic or capable of binding, their pharmacologically activederivatives or precursors of pharmacologically active substances may beused that release the actual active agent when in the tissue only.Preferred are cytostatics from the taxoid group such as paclitaxel anddocetaxel((2R,3S)-N-(tert-butoxycarbonyl)-2-hydroxy-3-phenyl-β-alan-ine-(4-acetoxy-2-α-benzoyloxy-5-β,20-epoxy-1,7-β,10-β-trihydroxy-9-oxo-11-taxene-13-α-yl-ester)),or epothilones as examples of lipophilic substances. These are solipophilic and insoluble in water that even more hydrophilic derivativesas described by Nicollaou K C, Riemer C, Kerr M A, Rideout D, WrasidloW. Design, Synthesis and biological activity of protaxols. Nature, 1993;364: pp. 464-466 or in U.S. Pat. No. 457,674, Novel Taxoids, arepreferred as long as their molecular weight does not exceed ca. 10 kD.

Other useful active agents are selected from the groups of corticoids,mitosis inhibitors such as colchicine, antibiotics such as azithromycinor roxithromycin (Gupta et al. 1998) or antioxidants such as probucol,as well as heparin and hirudin derivatives or prostacyclins.Furthermore, immunosuppressants such as rapamycin are among the activeagents that can be used.

Examples of lipophilic derivatives of otherwise hydrophilic cytostaticscan be found in Brunner H, Schellerer K-M, Treittinger B. Synthesis andin vitro testing of hematoporphyrin type ligands in platinum(II)complexes as potent cytostatic and phototoxic antitumor agents.Inorganica Chimica Acta, 1997; 264: pp. 67-79 in the form of conjugatesof platinum complexes with porphyrins.

The preparations according to the invention that contain a cytostatic asan active ingredient are also suitable for treating tumor diseases. Itis advantageous in this case that the treatment is local, whichminimizes the strain the patient is put under.

Besides lipophilic substances, other active agents or substrate-boundactive agents with a specific affinity to vessel walls, particularly tovessel walls showing pathological change, are suitable. Substances havea specific affinity to vessel walls when they are not washed away by thebloodstream within a few minutes. It is known that small concentrationsof magnetites are deposited after intravenous administration in vesselwalls that show arteriosclerotic change (Schmitz S A et al.Superparamagnetic iron oxide—enhanced MRI of atherosclerotic plaques inWatanabe hereditable hyperlipidemic rabbits. Invest Radiol, 2000; 35:460-471). However it is surprising that these magnetites reachconcentrations sufficient for treatment after a short-time flow throughthe vessels that are dilated using a balloon. To make these magnetitesusable for treatment, they must be coated with drugs as described, forexample, by Lubbe A S, Bergemann C, Huhnt W. Fricke T, Riess H, Brock JW, Huhn D. Preclinical experiences with magnetic drug targeting:Tolerance and efficacy. Cancer Research, 1996, 56: 4694-4701).

The active agents are dissolved as much as possible in the undilutedcontrast agents. They can also be prepared as a separate solution thatis diluted with contrast agents prior to use. The mixing ratio of activeagent solution and contrast agent solution should not be greater than2:1, preferably <1:1, <0.2:1 being particularly preferred. The activeagent should be dissolved in a well-tolerable aqueous medium or a mediumthat can be mixed with water. Also admissible are organic solvents thatare well tolerated (at least after being diluted with the contrast agentsolution or another aqueous medium) such as ethanol, DMSO, DMF, etc. Theprepared injection solution will mostly contain as great a portion ofwater as possible (>90 volume percent, preferred >95 volume percent, >99volume percent particularly preferred).

The concentration range of each active agent is dependent on theirsolubility in physiologically tolerable solvents without having toresort to micelle-forming agents such as cremophor and on the efficacyand tolerability of the active agents. The upper limit of theconcentration is always determined by the volume to be administered(e.g. 100 to 200 ml for repeated injection into the coronary arteries)and the maximum systemically tolerable dose (e.g. ca. 100 mg per sqmbody surface for paclitaxel). Preferred and sufficiently effective dueto local administration and action are dosages of 1/10th or less of themaximum systemically tolerable dose.

Other effective substances such as coagulation inhibitors, plateletaggregation inhibitors, enzyme inhibitors, complex-forming agents forcalcium ions, etc. may be added to the preparations. These do not haveto meet the criteria for lipophilia, binding to tissue components ormolecular weight as the effect can also be acute and intravascular; whathas been said in the paragraph regarding concentration and dosage aboveapplies here because the focus is on the local effect in the vesselsection through which the preparation flows.

Another way of administering antiproliferative agents is provided by acatheter used for vessel dilatation that has an inflatable balloon whichitself causes the vascular dilatation. The balloon can be coated withthe active agent. When the vessel is dilated, the balloon is pressedagainst the vessel wall. This provides an opportunity for the activeagent to transfer into the vessel wall. If the balloon is used to dilatea stent, even the active agent between the balloon and the stent can bereleased because the metal struts of the stent are displaced relative tothe balloon surface. These variations of active agent administration donot constitute an additional step for the physician as compared to theoriginal process of vessel dilatation or stent implantation.

The following methods can be used if the active agents are to be appliedto the part of the catheter that is used for vessel dilatation:Dissolution of the active agent(s) in a solvent that does not corrodethe catheter, immersion of the respective catheter part in the solution,removal of the catheter from the solution, and drying. Optionally,matrix or gel-forming adjuvants can be added to the active agentsolution in the vessel, e.g. lipides or polymers used in pharmacology.Coating can be performed in several steps, while agent-containing andagent-free layers may alternate. The solvents for the respective layersshould be selected in such a way that the subsequent coating does notstrip off the previous one.

The examples below shall explain the invention:

EXAMPLES Example 1a Solution for Direct Administration into the Arteries

80 mg of 7-(2″,3″-dihydroxypropyl oxycarbonyl)-paclitaxel are dissolvedin 5 ml of dimethyl sulfoxide and diluted with 5 ml of a 5% glucosesolution. The solution or a part thereof is slowly infused into thepreviously dilated arteries.

Example lb: X-ray Contrast Medium with an Additive for InhibitingIntimal Hyperplasia

99 parts of a portion of the solution described in 1a are added to theVisipaque 320, a commercial X-ray contrast medium, and immediately mixedwell. The solution can be used as is common for angiography prior to orafter vessel dilatation.

Example 2a Solution as an Additive to Contrast Agents

200 mg of 7-(2″,3″-dihydroxypropyl oxycarbonyl)-paclitaxel are dissolvedin 10 ml of absolute ethanol (=solution A); 0.35 ml of this solution canbe added to 100 ml of contrast agent.

Example 2b X-ray Contrast Medium for Restenosis Prevention

100 ml of Ultravist 370 (Schering AG, Berlin; active ingredientiopromide equivalent to 370 mg of iodine/ml) containing 0.35 volumepercent of ethanol and 7 mg of 7-(2″,3″-dihydroxypropyloxycarbonyl)-paclitaxel. The solution is produced by dissolving the7-(2″,3″-dihydroxypropyl oxycarbonyl)-paclitaxel in ethanol and addingit under constant stirring to the contrast agent.

Example 2c X-ray Contrast Medium for Restenosis Prevention

The preparation according to Example 2b with an addition of 10 I.U. oflow-molecular heparin

Example 2d Restenosis-inhibiting Perfusion Solution

3.5 ml of the solution A described in Example 2a are mixed with 46.5 mlof ethanol and added under fast shaking to 1000 ml of warm (−50 .degree.C.) 5% glucose solution or isotonic electrolyte solution. This solutionis infused via a catheter into the vessels to be treated just like acontrast medium; however, the infusion rate can be reduced as comparedto that of contrast agents.

Example 3a X-ray Contrast Medium for Inhibiting Intimal Hyperplasia

100 ml of Ultravist 370 (see Example 2b) mixed with 0.4 volume percentof ethanol and 14.4 mg of 7-(2″,3″-dihydroxypropyloxycarbonyl)-paclitaxel. The preparation is produced as described inExample 2b.

Example 4a X-ray Contrast Medium for Inhibiting Cell Growth

100 ml of Solutrast 370 (Byk-Gulden, Konstanz; active ingredientiopamidol equivalent to 370 mg of iodine/ml) containing 1.0 volumepercent of ethanol and 8.2 mg of paclitaxel/ml. The preparation isproduced by first dissolving the paclitaxel in absolute ethanol whileheating it slightly, then adding the contrast agent quickly and understrong stirring.

Example 4b X-ray Contrast Medium for Inhibiting Intimal Hyperplasia

Preparation according to Example 4a plus adding 5 I.U. of heparin and 5mmol/l of citrate buffer (pH 7.0).

Example 5a Solution as an additive to Contrast Agents or InfusionSolutions

20 mg of(±)-trans-1,2-diaminocyclohexane{7,12-bis[1-(1,4,7,10,1-3,16-hexaoxaheptadecyl)-ethyl]-3,8,13,17-tetramethylporphyrin-2,18-dipropionato}platinum(II)are dissolved in 10 ml of dimethyl sulfoxide (=solution B)

Example 5b X-ray Contrast Medium with an Additive for Inhibiting CellGrowth

1 ml of solution B is added under fast stirring to 100 ml of Ultravist370 (see Example 2b). The solution is suitable for infusion intoarteries or injection into living or dead tissues or body cavities. Itallows excellent control of its initial distribution and causes along-lasting cytostatic effect.

Example 5c Contrast Medium for Magnetic Resonance Tomography with anAdditive for Inhibiting Cell Growth

1 ml of solution B is added to 10 ml of 50 mmolar gadolinium DTPA(=gadopentetate) solution. A 50 mmolar gadolinium-DTPA solution isprepared from Magnevist, a commercial preparation (Schering AG, Berlin),by diluting the product ten times. The solution can be infiltrated, forexample, in vital tumors or in tumors after they were destroyed byethanol, heat or cold treatment. The distribution of the solution iswell visible in magnetic resonance tomograms. The solution itselfsupports the total destruction of the tumor in the immediatelyinfiltrated area and its vicinity.

Example 6 In-Vivo Efficacy of the Preparation as Described in Example 2b

2 coronary arteries each in a total of 8 pigs were dilated underanesthesia, and stents (fine, heavily perforated metal tubes) wereimplanted. The arteries respond by wall thickening, which results innarrowing the original lumen of the arteries. 4 pigs were administered aregular X-ray contrast agent (Ultravist 370) for imaging the arteriesand checking the stent implantation, 4 pigs were administered thepreparation according to Example 2b. The vessels of both test groupspractically had the same widths (inside diameters 3.4±0.2 mm and 3.5±0.2mm) immediately after treatment. 4 weeks after treatment, the insidearterial diameter in animals that only received the regular contrastagent had stenosed by 1.9±0.8 mm, whereas the arterial diameter in theanimals that were treated with the solution according to Example 2b wasonly reduced by 0.9±0.6 mm. This difference is statistically significant(p=0.01). The undiluted solution according to Example 2b was toleratedwithout side effects despite the addition of a high concentration of arelatively toxic cytostatic after injection in the coronary arteries andsimultaneous ECG and blood pressure measurements.

Example 7a Coating a Catheter

The distal area carrying the balloon of a balloon catheter designed forvessel dilatation is immersed under sterile conditions in the ethanolicsolutions from Example 2a (=solution A), kept in the solution for ca. 5minutes, then removed and dried for 2 hours at room temperature. Theballoon catheter can then be used in the common way for dilatingvessels.

Alternatively, a stent is placed on the balloon after drying.

Example 7b

The procedure is like in Example 7a, but 100 mg of pharmaceutical castoroil are now added to solution A.

Example 8a Solubility in the Contrast Agent or Physiological NaClSolution

7.6 mg of paclitaxel are dissolved in 0.5 mg of ethanol and added atroom temperature to 50 ml Ultravist-370 (contains 768 mg ofiopromide/ml, specific weight ca. 1.4 g/ml). A clear solution withoutany turbidity is obtained after mixing that remains stable for severaldays. No particles can be identified in the solution under a microscope.

4.2 mg of paclitaxel are dissolved in 0.5 ml of ethanol and added atroom temperature to 50 ml of a 0.9% NaCl solution. The preparationbecomes turbid immediately after mixing; most particles are found on thesurface of the solution after 2 hours. Large aggregations of fineparticles are found using a microscope.

EVALUATION

The solubility of paclitaxel in the contrast agent is highly surprising.The contrast agent solution contains 0.7 ml of water/ml of solutionmixture, i.e. Less solvent is available to paclitaxel in the contrastagent solution than in the NaCl solution. In spite of that, paclitaxeldissolves better in the contrast agent solution than in the NaClsolution.

Example 8b Magnetite as the Carrier of the Antihyperplastic Agent

75 mg of paclitaxel are dissolved in 5 ml of ethanol. The paclitaxelsolution is added to 50 ml of an aqueous preparation of a colloidalmagnetite coated with degraded dextrane (concentration refers toFe^(2+/3+)0.5 molar, e.g. SH U 555C, test preparation by Schering AG,Berlin) and quickly intermixed. The magnetite particles adsorbpaclitaxel and carry it after intravenous or intra-arterial injection,inter alia, into arterial walls showing arteriosclerotic change andbrain tumors. Dosage depends on the use of the magnetite and is ca. 50μmol referred to Fe/kg of body weight.

1. A preparation containing at least one antihyperplastic agent with adistribution ratio between butanol and water of ≧0.5 in liquid formsuitable for passing through capillaries together with an agent forenhancing artery/vein imaging.
 2. A preparation containing at least oneantihyper plastic agent with a distribution ratio between butanol andwater of ≧0.5 that is applied to a catheter.
 3. A preparation in aqueoussolution that may optionally contain additives as well as at least oneantihyperplastic agent with a distribution ratio between butanol andwater of ≧0.5 at a concentration that exceeds the saturationconcentration in the purely aqueous medium wherein the active agent isnot enclosed in micelles.
 4. The preparation according to claim 1wherein the antihyperplastic agent is a cytostatic, a corticoid, aprostacyclin, an antioxidant, an antibiotic, an agent inhibiting cellproliferation or an immunosuppressant.
 5. The preparation according toclaim 1 wherein the antihyperplastic agent is a taxoid.
 6. Thepreparation according to claim 1 wherein the antihyperplastic agent ispaclitaxel, docetaxel, probucol, a porphyrin derivative, colchicine orepithilone.
 7. The preparation according to claim 1 wherein the agentfor enhancing artery/vein imaging consists of solutions, suspensions oremulsions that the vessels can tolerate and that are used in Xraying,sonography, optical imaging, or magnetic resonance imaging for improvedrepresentation of the blood vessels or the bloodstream.
 8. Thepreparation according to claim 1 wherein the agent for enhancingartery/vein imaging is an X-ray contrast medium.
 9. The preparationaccording to claim 1 wherein the agent for enhancing artery/vein imagingis iodixanol (Visipaque), gadolinium-DTPA (Magnevist), Gd-DO3A-butrol(Gadovist), iopromide (Ultravist), iohexol (Omnipaque), or iopamidol(Solutrast)
 10. The preparation according to claim 1, characterized inthat the preparation additionally contains coagulation inhibitors and/orplatelet aggregation inhibitors and/or enzyme inhibitors and/or calciumchelators.
 11. The preparation according to claim 1 wherein the activeagent irreversibly or reversibly binds to tissue at a minimum percentageof 10%.
 12. The preparation according to claim 1 wherein the activeagent or the component carrying the active agent comprises a specificaffinity to vascular walls.
 13. The preparation according to claim 1wherein the preparation contains a solubility promoter that does notform micelles.
 14. Use of the preparation according to claim 1 forrestenosis prevention.
 15. Use of the preparation according to claim 1for treating tumor diseases.